More than 60% of individuals treated for alcohol use disorders (AUD) relapse within 6 months of treatment. The primary goal of this competitive renewal is to determine salient neurobiological and neuropsychological factors that predict relapse to hazardous alcohol consumption in individuals treated for AUD. Identification of such relapse risk factors is pivotal for a better understanding of mechanisms of relapse and sustained abstinence and will facilitate identification of individuals with greatest relapse vulnerability. Sch knowledge will ultimately inform the development of more personalized interventions to increase the efficacy of AUD treatment and reduce alcohol-related mortality. In the current grant period, via state-of-the-art magnetic resonance (MR) methods and neurocognitive assessments, we have demonstrated that concurrent chronic cigarette smoking in treatment seeking alcoholics (ALC) is associated with compounded neurobiological and neurocognitive dysfunction. We have further shown that neurobiological and neurocognitive recovery during abstinence from alcohol is hampered by chronic cigarette smoking. In addition, preliminary retrospective analyses revealed that regional measures of brain morphology, neuronal integrity and blood flow as well as processing speed early in sobriety discriminated individuals who maintained sobriety (abstainers) from those who resumed hazardous drinking within 12 months following treatment (relapsers). Some of these measures also significantly predicted relapse, and MR-based neurobiological measures of components of the brain reward system (BRS) were strongly related to the severity of post-treatment alcohol consumption in relapsers. In this revised renewal, we postulate that neurobiological abnormalities in brain regions that include the 'top-down' components of the BRS and related neurocognitive deficits in executive skills, reward-related decision-making, risk taking, impulse control, and processing speed predict relapse within 1 year following treatment for AUD. We propose to study longitudinally over three months 100 ALC by state-of-the-art high-field MR methods (metabolite concentrations, morphology, perfusion, diffusion), measurements of reward-related decision-making, risk taking, impulse control and other neurocognitive domains, to quantitate alcohol consumption over 12 months following treatment, and to collect DNA for banking and select genotyping to explore the relapse phenotype. We will then determine what cross-sectional measures at baseline and 3-month-follow-up and what longitudinal change measures distinguish future relapsers from future abstainers, and determine which of these factors or combinations thereof accurately predict relapse vs. abstinence. This research will establish a more comprehensive and integrated biopsychosocial relapse risk profile for AUD individuals and subgroups. The research is of high clinical significance in AUD treatment, as it will provide critical new information for focusing limited treatment resources on those with greatest relapse vulnerability, thereby increasing overall AUD treatment efficacy and reducing mortality in AUD. PUBLIC HEALTH RELEVANCE: The main goal of this competitive renewal is to identify new neurobiological and neuropsychological factors that relate to increased risk for relapse in individuals seeking treatment for alcohol use disorders. These factors and some exploratory candidate genotypes will then be evaluated as to their ability to serve as practical clinical predictors of relapse after treatment, potentially enhancing known psychosocial predictors of relapse risk. The successful research will allow developing novel treatment strategies that focus limited resources on those at greatest risk for relapse after substance abuse treatment.